Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 57. Heavy Metals

Heavy Metals: Introduction

The heavy metals discussed in this chapter—lead, arsenic, mercury, and iron—frequently cause toxicity in humans. The toxicity profiles of metals differ, but most of their effects appear to result from interaction with sulfhydryl groups of enzymes and regulatory proteins. Chelators are organic compounds with 2 or more electronegative groups that form stable bonds with cationic metal atoms. These stable complexes lack the toxicity of the free metals and often are excreted readily. Chelators, which function as chemical antagonists, are used as antidotes in the treatment of heavy metal poisoning.

High-Yield Terms to Learn

Chelating agent A molecule with 2 or more electronegative groups that can form stable coordinate complexes with multivalent cationic metal atoms Erethism Syndrome resulting from mercury poisoning characterized by insomnia, memory loss, excitability, and delirium Pica The ingestion of nonfood substances; in the present context, pica refers to ingestion of lead-based paint fragments by small children Plumbism A range of toxic syndromes due to chronic lead poisoning that may vary as a function of blood or tissue levels and patient age

Toxicology of Heavy Metals

Lead

Lead serves no useful purpose in the body and can damage the hematopoietic tissues, liver, nervous system, kidneys, gastrointestinal tract, and reproductive system (Table 57-1). Lead is a major environmental hazard because it is present in the air and water throughout the world.

TABLE 57-1 Important characteristics of the toxicology of arsenic, iron, lead, and mercury.

Metal Form Entering Body Route of Absorption Target Organs for Toxicity Treatmenta

Lead Inorganic lead oxides and salts Tetraethyl lead Gastrointestinal, respiratory, skin (minor) Skin (major), gastrointestinal Hematopoietic system, CNS, kidneys CNS Dimercaprol, EDTA, succimer, unithiol Seizure control, supportive Arsenic Inorganic arsenic salts All mucous surfaces Capillaries, gastrointestinal tract, hematopoietic system Dimercaprol, unithiol, succimer, penicillamine Arsine gas Inhalation Erythrocytes Supportive Mercury Elemental Inorganic salts Inhalation Gastrointestinal CNS, kidneys Kidneys, gastrointestinal tract Succimer, unithiol Succimer, unithiol, penicillamine, dimercaprol Organic mercurials Gastrointestinal CNS Supportive Iron Ferrous sulfate Gastrointestinal Gastrointestinal, CNS, blood Deferoxamine

aIn all cases, removal of the person from the source of toxicity is the first requirement of management.

Acute Lead Poisoning

Because of the ban on lead over 20 yrs ago in gasoline and because of bans on other industrial products that previously contained lead, acute inorganic lead poisoning is no longer common in the United States. It can occur rarely from industrial exposures (usually via the inhalation of dust) and in children who have ingested large quantities of chips or flakes from surfaces in older houses covered with lead-containing paint. The primary signs of this syndrome are acute abdominal colic and central nervous system (CNS) changes, including, particularly in children, acute encephalopathy. The mortality rate is high in those with lead encephalopathy, and prompt chelation therapy is mandatory.

Chronic Lead Poisoning

Chronic inorganic lead poisoning (plumbism) is much more common than the acute form. Signs include peripheral neuropathy (wrist-drop is characteristic), anorexia, anemia, tremor, weight loss, and gastrointestinal symptoms. Treatment involves removal from the source of exposure, and chelation therapy, usually with oral succimer in outpatients and with parenteral agents (eg, EDTA with or without dimercaprol) in more severe cases. Chronic lead poisoning in children presents as growth retardation, neurocognitive deficits, and developmental delay. Succimer is generally used in such children. In workers exposed to lead, prophylaxis with oral chelating agents is contraindicated because some evidence suggests that lead absorption may be enhanced by the presence of chelators. In contrast, high dietary calcium is indicated because it impedes lead absorption.

Organic Lead Poisoning

Now rare, poisoning by organic lead was usually due to tetraethyl lead or tetramethyl lead contained in "antiknock" gasoline additives, which are no longer used. This form of lead is readily absorbed through the skin and lungs. The primary signs of intoxication include hallucinations, headache, irritability, convulsions, and coma. Treatment consists of decontamination and seizure control.

Arsenic

Arsenic is widely used in industrial processes and is also an environmental pollutant released during the burning of coal. Although the element exists in both trivalent and pentavalent forms, its toxicity is entirely due to the trivalent form.

Acute Arsenic Poisoning

Acute arsenic poisoning results in severe gastrointestinal discomfort, vomiting, "rice-water" stools, and capillary damage with dehydration and shock. A sweet, garlicky odor may be detected in the breath and the stools. Treatment consists of supportive therapy to replace water and electrolytes, and chelation therapy with dimercaprol.

Chronic Arsenic Poisoning

Chronic arsenic intoxication causes skin changes, hair loss, bone marrow depression and anemia, and chronic nausea and gastrointestinal disturbances. Dimercaprol therapy appears to be of value. Arsenic is a known human carcinogen.

Arsine Gas

Arsine gas (AsH 3), an occupational hazard, is formed during the refinement and processing of certain metals and is used in the semiconductor industry. Arsine causes a unique form of toxicity characterized by massive hemolysis. Pigment overload from erythrocyte breakdown can cause renal failure. Treatment is supportive.

Mercury

The main source of inorganic mercury as a toxic hazard is through the use of mercury-containing materials in dental laboratories and in the manufacture of wood preservatives, insecticides, and batteries. Organic mercury compounds are used as seed dressings (treatments to prevent fungal and bacterial infection of seed and to improve the seed's dispersion and adhesiveness) and fungicides.

Acute Mercury Poisoning

Acute mercury poisoning usually occurs through inhalation of inorganic elemental mercury. It causes chest pain, shortness of breath, nausea and vomiting, kidney damage, gastroenteritis, and CNS damage. In addition to intensive supportive care, prompt chelation with oral succimer or with intramuscular dimercaprol is essential. Acute ingestion of mercuric chloride causes a severe, life-threatening hemorrhagic gastroenteritis followed by renal failure.

Chronic Mercury Poisoning

Chronic mercury poisoning may occur with inorganic or organic mercury. Poisoning from inhalation of mercury vapor presents as a diffuse set of symptoms involving the gums and teeth, gastrointestinal disturbances, and neurologic and behavioral changes (erethism). Chronic mercury intoxication has been treated with succimer and unithiol, but their efficacy has not been established. Dimercaprol may redistribute mercury to the CNS and should not be used in chronic exposure to elemental mercury.

Organic Mercury Poisoning

Intoxication with organic mercury compounds was first recognized in connection with an epidemic of neurologic and psychiatric disease in the village of Minamata, Japan, which was first noticed in the 1950s. The outbreak was a result of consumption of fish containing a high content of methylmercury, which was produced by bacteria in seawater from mercury in the effluent of a nearby vinyl plastics-manufacturing plant. Similar epidemics have resulted from the consumption of grain that was intended for use as seed and treated with fungicidal organic mercury compounds. Treatment with chelators has been tried, but the benefits are uncertain.

Iron

Acute poisoning from the ingestion of ferrous sulfate tablets occurs frequently in small children, although the incidence of poisonings dropped dramatically in the United States after iron supplements were required to be packed in unit-dose packing. The initial symptoms of iron poisoning include vomiting, gastrointestinal bleeding, lethargy, and gray cyanosis. These can be followed by signs of severe gastrointestinal necrosis, pneumonitis, jaundice, seizures, and coma. Deferoxamine is the chelating agent of choice. Chronic excessive intake of iron can lead to hemosiderosis or hemochromatosis (see Chapter 33).

Skill Keeper: Iron Deficiency

(See Chapter 33)

Iron is the essential metallic element of heme, the molecule responsible for the bulk of oxygen transport in the blood.

1. How is the iron content of the body regulated?

2. How is iron deficiency diagnosed and treated?

The Skill Keeper Answers appear at the end of the chapter.

Chelators

Chelators used clinically include dimercaprol (BAL), succimer, unithiol, penicillamine, edetate (EDTA), and deferoxamine. Variations among these agents in their affinities for specific metals govern their clinical applications (Table 57-1).

Dimercaprol

Dimercaprol (2,3-dimercaptopropanol; BAL [British antilewisite]) is a bidentate chelator; that is, a chelator that forms 2 bonds with the metal ion, preventing the metal's binding to tissue proteins and permitting its rapid excretion.

Clinical Use

Dimercaprol is used in acute arsenic and mercury poisoning and, in combination with EDTA, for lead poisoning. It is an oily liquid that must be given parenterally.

Toxicity

Dimercaprol causes a high incidence of adverse effects, possibly because it is highly lipophilic and readily enters cells. Its toxicity includes transient hypertension, tachycardia, headache, nausea and vomiting, paresthesias, and fever (especially in children). It may cause pain and hematomas at the injection site. Long-term use is associated with thrombocytopenia and increased prothrombin time.

Succimer

Succimer (2,3-dimercaptosuccinic acid; DMSA) is a water-soluble bidentate congener of dimercaprol.

Clinical Use

Succimer is used for the oral treatment of lead toxicity in children and adults. It is as effective as parenteral EDTA in reducing blood lead concentration. Succimer is also effective in arsenic and mercury poisoning, if given within a few hours of exposure.

Toxicity

Although succimer appears to be less toxic than dimercaprol, gastrointestinal distress, CNS effects, skin rash, and elevation of liver enzymes may occur.

Unithiol

A water-soluble derivative of dimercaprol, unithiol can be administered orally or intravenously.

Clinical Use

Intravenous unithiol is used in the initial treatment of severe acute poisoning by inorganic mercury or arsenic. Oral unithiol is an alternative to succimer in the treatment of lead intoxication.

Toxicity

Unithiol causes a low incidence of dermatological reactions, usually mild. Vasodilation and hypotension may occur with rapid intravenous infusion.

Penicillamine

Penicillamine, a derivative of penicillin, is another bidentate chelator.

Clinical Use

The major uses of penicillamine are in the treatment of copper poisoning and Wilson's disease. It is sometimes used as adjunctive therapy in gold, arsenic, and lead intoxication and in rheumatoid arthritis. The agent is water-soluble, well absorbed from the gastrointestinal tract, and excreted unchanged.

Toxicity

Adverse effects are common and may be severe. They include nephrotoxicity with proteinuria, pancytopenia, and autoimmune dysfunction, including lupus erythematosus and hemolytic anemia.

Ethylenedinitrilotetraacetic Acid

Ethylenedinitrilotetraacetic acid (EDTA) (edetate) is an efficient polydentate chelator of many divalent cations, including calcium, and trivalent cations.

Clinical Use

The primary use of EDTA is in the treatment of lead poisoning. Because the agent is highly polar, it is given parenterally. To prevent dangerous hypocalcemia, EDTA is usually given as the calcium disodium salt.

Toxicity

The most important adverse effect of the agent is nephrotoxicity, including renal tubular necrosis. This risk can be reduced by adequate hydration and restricting treatment with EDTA to 5 d or less. Electrocardiographic changes can occur at high doses.

Deferoxamine and Deferasirox

Deferoxamine is a polydentate bacterial product that has an extremely high and selective affinity for iron and a much lower affinity for aluminum. Fortunately, the drug competes poorly for heme iron in hemoglobin and cytochromes. Deferasirox is a newer tridentate chelator with selectively high affinity for iron.

Clinical Use

Deferoxamine is used parenterally in the treatment of acute iron intoxication and in the treatment of iron overload caused by blood transfusions in patients with diseases such as thalassemia or myelodysplastic syndrome (see Chapter 33). Deferasirox is an oral drug approved for treatment of iron overload.

Toxicity

Skin reactions (blushing, erythema, urticaria) may occur. With long-term use, neurotoxicity (eg, retinal degeneration), hepatic and renal dysfunction, and severe coagulopathies have been reported. Rapid intravenous administration of deferoxamine can cause histamine release and hypotensive shock.

Skill Keeper Answers: Iron Deficiency

(See Chapter 33)

1. Regulation of total body iron occurs through a tightly regulated system of intestinal absorption. Ferrous iron is absorbed and either stored in mucosal cells as ferritin or transported into blood and distributed throughout the body bound to transferrin. Most of the iron in the body is present in hemoglobin. Small quantities of iron are eliminated in sweat, saliva, and the exfoliation of skin and mucosal cells

2. Iron deficiency can be diagnosed from red blood cell changes, including microcytic size, and decreased hemoglobin content, and from measurement of serum and bone marrow iron stores. Iron deficiency anemia is treated by dietary oral ferrous iron supplements or, in severe cases, parenteral administration of a colloid containing a core of iron oxyhydroxide surrounded by a core of carbohydrate.

Checklist

When you complete this chapter, you should be able to:

 Describe the general mechanism of metal chelation.

 Identify the clinically useful chelators and know their indications and their adverse effects.

 Describe the major clinical features and treatment of acute and chronic lead poisoning.

 Describe the major clinical features and treatment of arsenic poisoning.

 Describe the major clinical features and treatment of inorganic and organic mercury poisoning.

 Describe the major clinical features and treatment of iron poisoning.



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